NM_000552.5(VWF):c.2561G>A (p.Arg854Gln) AND Hereditary von Willebrand disease

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Mar 19, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000169683.23

Allele description [Variation Report for NM_000552.5(VWF):c.2561G>A (p.Arg854Gln)]

NM_000552.5(VWF):c.2561G>A (p.Arg854Gln)

Gene:

VWF:von Willebrand factor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12p13.31

Genomic location:

Preferred name:

NM_000552.5(VWF):c.2561G>A (p.Arg854Gln)

Other names:

p.R854Q

HGVS:

NC_000012.12:g.6034812C>T
NG_009072.2:g.94859G>A
NM_000552.5:c.2561G>AMANE SELECT
NM_000552.5:c.2561G>A
NP_000543.2:p.Arg854Gln
NP_000543.3:p.Arg854Gln
LRG_587t1:c.2561G>A
LRG_587:g.94859G>A
LRG_587p1:p.Arg854Gln
NC_000012.11:g.6143978C>T
NC_000012.12:g.6034812C>T
NG_009072.1:g.94859G>A
NM_000552.2:c.2561G>A
NM_000552.3:c.2561G>A
NM_000552.4:c.2561G>A
P04275:p.Arg854Gln

Protein change:

R854Q; ARG854GLN

Links:

UniProtKB: P04275#VAR_005789; OMIM: 613160.0013; dbSNP: rs41276738

NCBI 1000 Genomes Browser:

rs41276738

Molecular consequence:

NM_000552.5:c.2561G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary von Willebrand disease
Identifiers:: MONDO: MONDO:0019565; MeSH: D014842; MedGen: C5703318

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000221221	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 19, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 1832934, 1581215, 21371195, 23426949, 23636243, 25741868
SCV000380622	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification 20161018)	Pathogenic (Jun 14, 2016)	germline	clinical testing	PubMed (15) [See all records that cite these PMIDs] 1832934, 1906877, 22875612, 18712522, 1918030, 8500791, 22197721, 16985174, 1581215, 23426949, 23636243, 21371195, 16953269, 15461624, 20409624 ICSL_Variant_Classification_20161018.pdf, Citation Link,
SCV000899325	NIHR Bioresource Rare Diseases, University of Cambridge - ThromboGenomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 1, 2019)	unknown	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 31064749
SCV002507237	GeneReviews	no classification provided	not provided	germline	literature only

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, literature only
not provided	unknown	yes	2	not provided	not provided	2	not provided	research
European	unknown	yes	8	not provided	not provided	8	not provided	research

Citations

PubMed

Identification of two point mutations in the von Willebrand factor gene of three families with the 'Normandy' variant of von Willebrand disease.

Gaucher C, Mercier B, Jorieux S, Oufkir D, Mazurier C.

Br J Haematol. 1991 Aug;78(4):506-14.

PubMed [citation]

PMID:: 1832934

Molecular characterization of a unique von Willebrand disease variant. A novel mutation affecting von Willebrand factor/factor VIII interaction.

Cacheris PM, Nichols WC, Ginsburg D.

J Biol Chem. 1991 Jul 25;266(21):13499-502.

PubMed [citation]

PMID:: 1906877

See all PubMed Citations (17)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000221221.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

The p.Arg854Gln has been reported in the homozygous or compound heterozygous state in >20 individuals with von Willebrand disease (VWD) type 2N (Gaucher 1991 PMID: 1832934, Peerlinck 1992 PMID: 1581215, Veyradier 2011 PMID: 21371195). This variant is a common disease-causing variant for type 2N VWD (Casonato 2013 PMID: 22875612). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 296) and has been identified in 0.6% (7050/1180026) of European chromosomes, including 26 total homozygotes by gnomAD (http://gnomad.broadinstitute.org, v.4.0.0). This is consistent with a recessive carrier frequency and the clinical manifestations of type 2N VWD. In vitro functional studies indicate the p.Arg854Gln variant may affect protein function as it has been shown to decrease binding to factor VIII (Wang 2012 PMID: 23426949, Skipwith 2013 PMID: 23636243). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive type 2N von Willebrand disease. ACMG/AMP criteria applied: PM3_VeryStrong, PS3_Supporting, PM2_Supporting.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV000380622.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (15)

Description

The c.2561G>A (p.Arg854Gln) variant is found specifically in patients with type 2N von Willebrand disease (VWD) which manifests as a mild form of VWD with only moderate bleeding in homozygotes. This variant is well-documented as disease-causing for this specific type of VWD, found in up to 73% of type 2N patients to date (Casonato et al. 2013). The variant is also common among Caucasians, being found in over 1% of the general population (Goodeve et al. 2010). Across a selection of the available literature, the p.Arg854Gln variant has been reported in seven studies and found in a total of 72 patients including in 26 in a homozygous state, 12 in a compound heterozygous state and 34 in a heterozygous state in whom a second variant as not been found (Gaucher et al. 1991; Cacheris et al. 1991; Peerlinck et al. 1992; Hilbert et al. 2004; Hilbert et al. 2006; Veyradier et al. 2011; Casonato et al. 2013). The variant was absent from 906 control alleles and is reported at a frequency of 0.014 in the Puerto Rican population of the 1000 Genomes Project. Functional studies have demonstrated that the p.Arg854Gln variant results in reduced binding of FVIII and proteolysis by ADAMTS13 with a normal multimer pattern (Gaucher et al. 1991; Cacheris et al. 1991; Peerlinck et al. 1992; Hilbert et al. 2004; Hilbert et al. 2006; Skipwith et al. 2013; Wang et al. 2013). Based on the collective evidence, the p.Arg854Gln variant is classified as pathogenic for von Willebrand disease.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From NIHR Bioresource Rare Diseases, University of Cambridge - ThromboGenomics, SCV000899325.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	PubMed (2)
2	not provided	1	not provided	not provided	research	PubMed (2)
3	European	1	not provided	not provided	research	PubMed (2)
4	European	1	not provided	not provided	research	PubMed (2)
5	European	1	not provided	not provided	research	PubMed (2)
6	European	1	not provided	not provided	research	PubMed (2)
7	European	1	not provided	not provided	research	PubMed (2)
8	European	1	not provided	not provided	research	PubMed (2)
9	European	1	not provided	not provided	research	PubMed (2)
10	European	1	not provided	not provided	research	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	1	not provided	not provided		1	not provided	not provided	not provided
2	unknown	yes	1	not provided	not provided		1	not provided	not provided	not provided
3	unknown	yes	1	not provided	not provided		1	not provided	not provided	not provided
4	unknown	yes	1	not provided	not provided		1	not provided	not provided	not provided
5	unknown	yes	1	not provided	not provided		1	not provided	not provided	not provided
6	unknown	yes	1	not provided	not provided		1	not provided	not provided	not provided
7	unknown	yes	1	not provided	not provided		1	not provided	not provided	not provided
8	unknown	yes	1	not provided	not provided		1	not provided	not provided	not provided
9	unknown	yes	1	not provided	not provided		1	not provided	not provided	not provided
10	unknown	yes	1	not provided	not provided		1	not provided	not provided	not provided

From GeneReviews, SCV002507237.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 20, 2024

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